ABSTRACT Digital mammography (DM) combined with digital breast tomosynthesis (DBT) has emerged as a promising primary breast cancer screening technology with improvements in specificity and sensitivity compared to screening with DM alone. However, the total radiation dose of a combined DM/DBT study is often twice that of screening with DM alone, raising concerns about the cumulative dose over a lifetime of screening. In 2013, the FDA approved synthetic ?2D-like? (s2D) images, derived from data acquired during the DBT acquisition, as a replacement for the conventional ?dose? DM imaging in DBT screening. Our preliminary single site data and early reader studies suggest that s2D/DBT screening may further reduce recall and biopsy rates compared to DM/DBT, while providing high invasive breast cancer detection rates but reduced detection of ductal carcinoma in situ (DCIS). In addition, the mammographic density assignments from s2D/DBT screening changed significantly with less patients deemed ?dense?, which could impact risk assessment and density-based clinical decisions regarding supplemental screening since breast density notification is mandated by laws in more than half of US states. We propose a multi-center observational study with adequate power to comprehensively characterize multiple aspects of s2D/DBT screening performance. We will leverage a natural experiment at early adopter radiology facilities participating in the University of Vermont and University of Pennsylvania PROSPR Research Centers that have transitioned from DM/DBT to s2D/DM for routine screening. Our specific aims are 1) To determine the clinical screening performance (e.g., sensitivity and specificity) of breast cancer screening with s2D/DBT; 2) To evaluate the rates of specific malignant and benign lesions detected by breast cancer screening with s2D/DBT; and 3) To determine the distribution of mammographic breast density assessments on s2D/DBT exams. For all aims, we will compare s2D/DBT screening performance to the performance of DM/DBT screening at the same facilities prior to their adoption of s2D/DBT. We anticipate a sample size of approximately 86,000 s2D/DBT exams and 98,000 DM/DBT exams. The University of Vermont and University of Pennsylvania PROSPR Research Centers have prospectively collected breast cancer screening data since 2011 in a standardized fashion to permit pooled analyses. Our registries contain exam- level breast imaging common data elements, including high quality information on indication of exam (i.e., screening vs. diagnostic), mammographic views, assessments, and breast density, linked to pathology databases and statewide cancer registries thereby permitting investigation of both benign and malignant diagnoses. The results of this project will provide needed evidence for women evaluating screening options, providers assessing whether to adopt s2D/DBT, health care payers considering reimbursement rates, and policy makers debating breast cancer screening recommendations in the context of this new technology.